Design and Folding of Dimeric Proteins

TL;DR

This study uses lattice models and simulations to explore how different evolutionary pressures influence the folding pathways of homodimeric proteins, revealing two distinct mechanisms consistent with experimental data.

Contribution

It demonstrates how the distribution of conserved amino acids affects dimer folding pathways, providing a theoretical framework aligned with observed protein behaviors.

Findings

Strongly conserved amino acids lead to a three-state folding process.

Distributed conservation results in a two-state, induced dimerization.

Model predictions align with conservation patterns in real proteins.

Abstract

In a similar way in which the folding of single--domain proteins provide an important test in the study of self--organization, the folding of homodimers constitute a basic challenge in the quest for the mechanisms which are at the basis of biological recognition. Dimerization is studied by following the evolution of two identical 20--letter amino acid chains within the framework of a lattice model and using Monte Carlo simulations. It is found that when design (evolution pressure) selects few, strongly interacting (conserved) amino acids to control the process, a three--state folding scenario follows, where the monomers first fold forming the halves of the eventual dimeric interface independently of each other, and then dimerize ("lock and key" kind of association). On the other hand, if design distributes the control of the folding process on a large number of (conserved) amino acids, a two--state folding scenario ensues, where dimerization takes place at the beginning of the proces, resulting in an "induced type" of association. Making use of conservation patterns of families of analogous dimers, it is possible to compare the model predictions with the behaviour of real proteins. It is found that theory provides an overall account of the experimental findings.